2025 Volume 72 Issue 4 Pages 365-373
Although antithyroid drugs (ATDs) are the first-line treatment for patients with Graves’ disease (GD) in Japan and other countries, some patients do not achieve remission due to drug resistance, leading to surgery. Even if ATD doses are increased, they often have uncontrolled thyroid function and enlarged goiters, necessitating high-risk emergency surgical treatment. In this study, we aimed to identify the characteristics of patients resistant to ATDs who underwent thyroidectomy and those who achieved remission. We retrospectively analyzed 45 patients with GD who underwent thyroidectomy and 73 patients who achieved remission with ATDs at Shinshu University Hospital between April 1, 2015 and September 30, 2023. In patients who underwent surgery, the drug-resistant patients (DR group; n = 15) had longer disease durations (8.0 vs. 3.0 years, respectively; p = 0.013), higher free triiodothyronine (FT3) / free thyroxine (FT4) ratios (5.54 vs. 3.52, respectively; p = 0.005), higher anti-TSH receptor antibody (TRAb) levels (39.16 vs. 13.31 IU/L, respectively; p = 0.002), and larger thyroid glands (251.00 vs. 54.80 g, respectively; p < 0.001) than non-drug-resistant patients (NDR group; n = 30). Compared with patients who achieved remission with ATDs (Remission group; n = 73), the DR group had higher FT3/FT4 ratios (5.54 vs. 2.99, respectively; p < 0.001) and higher TRAb levels (39.16 vs. 5.9 IU/L, respectively; p < 0.001). Notably, most of the patients in the DR group had a combination of these factors. This suggests that in patients with large thyroid, high FT3/FT4 ratios, and high TRAb levels, early consideration of definitive-curative treatment such as surgery or RI therapy may be warranted instead of continuing prolonged ineffective ATDs treatment.
Graves’ disease (GD) is caused by thyroid autoimmunity. When TSH receptors expressed on the thyroid membrane are continuously stimulated by anti-TSH receptor antibodies (TRAb), the thyroid gland becomes diffusely swollen and secretes large amounts of the thyroid hormones triiodothyronine (T3) and, thyroxine (T4). Thyroid hormones can cause thyrotoxicity throughout the body. Currently, the primary treatments for GD include antithyroid drugs (ATDs), radioactive iodine (RI) therapy, and surgery. Although these treatments are equally effective in normalizing thyroid hormones within 6 weeks [1], ATDs are the preferred first-line treatment for most patients with GD in Japan [2] and Europe [3]. There is no definitive standard for when to discontinue treatment with ATDs. If remission is not achieved after 18 months (1.5 years) of ATD treatments, it is generally considered that further continuation of ATDs may not lead to remission; consequently, surgical or RI therapy may be recommended. However, in cases where thyroid hormone levels can be controlled with low-dose ATDs, ATD therapy can be continued if the patient wishes [4]. In contrast, some patients continue long-term ATD treatment (≥1.5 years) without achieving remission; hence, they require surgery. These patients often have uncontrolled thyroid function and bulky goiters even after increasing ATDs doses, resulting in the need for emergency treatment. Such patients have particularly strong drug resistance. However, surgical treatments could have been avoided if patients likely to develop strong ATD resistance had been identified earlier. To the best of our knowledge, few reports have described the characteristics of patients who underwent thyroidectomy due to ATD resistance.
Therefore, in this study, we retrospectively examined patients who underwent surgical treatment for GD and those who achieved remission with ATDs, and identified the characteristics of patients who were resistant to ATD treatment leading to inevitable surgery.
This study enrolled 45 patients who underwent surgical treatment for GD at Shinshu University Hospital between April 1, 2015 and September 30, 2023. This study was approved by the Ethical Committee of the Shinshu University Graduate School of Medicine (approval number: 6154) and optout disclosure was provided.
The diagnosis of GD was made according to the 2021 Thyroid Disease Diagnosis Guidelines of the Japan Thyroid Association [5]. This included when there were clinical signs of thyrotoxicosis such as tachycardia, weight loss, finger tremors, and increased sweating; diffuse thyroid enlargement; exophthalmos; or specific eye symptoms. Moreover, the following four test findings had to be present: high levels of either free-T4 (FT4) or free-T3 (FT3), or both; low TSH levels (≤0.1 μU/mL); positive TRAb or thyroid stimulating antibody (TSAb) levels; and in typical cases, high levels of RI (or technetium) thyroid uptake and diffuse accumulation on scintigraphy. Because probable GD can be diagnosed without performing RI (or technetium) thyroid uptake or scintigraphy, probable GD cases were also included in this study.
Additionally, to further examine the characteristics of the drug-resistance group, 73 patients who received treatment with ATDs for GD and achieved remission at Shinshu University Hospital during the study period, were extracted as the remission group. Hence, the remission group was defined as those who no longer required medical treatment for GD 6 months after discontinuing ATDs administration.
Anthropometric and biochemical parametersPatient information on the following variables was obtained: age at the time of surgery, sex, body mass index (BMI), disease duration, reasons for surgery, thyroid hormone levels (FT3, FT4, TSH, and the FT3 divided by the FT4 [FT3/FT4 ratio]), at the time of maximum FT3 value, TRAb, anti-thyroglobulin antibody (TgAb), anti-thyroid peroxidase antibody (TPOAb), daily amount of thiamazole (MMI) immediately before surgery, and weight of thyroid gland after surgical removal. The reasons for undergoing surgery were extracted from the medical records. The weight of the thyroid gland was measured at the time of surgery.
The patients’ serum levels of TSH, FT3, FT4, and TRAb were measured using a chemiluminescent immunoassay kit (Cobas pro e801; Roche Diagnostics, Tokyo, Japan). The reference ranges were 0.5000–5.000 μIU/mL for TSH, 2.30–4.00 pg/mL for FT3, and 0.90–1.70 ng/dL for FT4. The normal range of TRAb is less than 1.30 IU/L. The serum levels of TgAb and TPOAb were measured using a chemiluminescent immunoassay kit (AIA-CL1200; TOSOH BIOSCIENCE, Tokyo, Japan). The normal ranges were less than 40.6 IU/mL for TgAb and less than 5.2 IU/mL for TPOAb. A TSH level less than 0.005 μIU/mL was considered as 0.005 μIU/mL, a FT3 level more than 32.55 ng/dL was considered as 32.55 ng/dL, and a FT4 level more than 7.77 ng/dL was considered as 7.77 ng/dL. In some patients, because the time of GD onset was unclear, the duration of GD that could be extracted from the medical records was regarded as the total duration of GD.
Statistical analysisData are expressed as median and interquartile ranges (IQR) (25–75th percentiles). Differences between groups were tested using the Mann-Whitney U-test for variables with skewed distributions and using the χ2 test for qualitative variables. The correlation between two variables was tested using simple correlation coefficients. All analyses were performed using StatFlex software version 7. A p-value of less than 0.05 was considered statistically significant.
The baseline demographics and characteristics of patients who underwent surgery are presented in Table 1. The median age of the patients was 50 (IQR: 30–58) years, and the median duration of GD was 4.0 (IQR: 1.0–13.0) years. The proportion of women was 73.3%. The median BMI at the first visit to our hospital was 21.8 (IQR: 20.0–24.1) kg/m2. The median of thyroid related data at the time of maximum FT3 levels were FT3 14.80 (IQR: 6.51–20.00) pg/mL, FT4 3.01 (IQR: 1.90–5.91) ng/dL, TSH 0.005 (IQR: 0.005–0.005) μIU/mL, and FT3/FT4 ratio 4.05 (IQR: 3.15–5.54). The median TRAb titer 25.34 (IQR: 9.04–53.00) IU/L, which was measured in 45 cases. The median amount of MMI used before surgical treatment was 20.0 (IQR: 15.0–30.0) mg, which was used in 29 patients. Total thyroidectomy was performed in all the patients. The median weight of the removed thyroid gland was 90.78 (IQR: 38.61–215.00) g and was measured in 38 patients.
| Patients’ characteristics and parameter | Number of patients or median [IQR] |
|---|---|
| Female, n | 33 (73.3%) |
| Age at surgical treatment, y | 50 [30–58] |
| Disease duration†, y | 4.0 [1.0–13.0] |
| BMI at first visit to our hospital, kg/ m2 | 21.8 [20.0–24.1] |
| Thyroid hormone levels at the maximum FT3 value | |
| TSH‡, μIU/mL | 0.005 [0.005–0.005] |
| FT3‡, pg/mL | 14.80 [6.51–20.00] |
| FT4‡, ng/dL | 3.01 [1.90–5.91] |
| FT3/FT4 | 4.05 [3.15–5.54] |
| Antibody status | |
| TRAb, IU/L (n = 45) | 25.34 [9.04–53.00] |
| TgAb, IU/mL (n = 38) | 37.8 [14.7–321.6] |
| TPOAb, IU/mL (n = 36) | 139.55 [5.75–526.00] |
| Amount of MMI used before surgical treatment, mg (n = 29) | 20.0 [15.0–30.0] |
| Total thyroidectomy, n | 45 (100.0%) |
| Thyroid weight, g (n = 38) | 90.78 [38.61–215.00] |
Abbreviations: IQR, interquartile range; BMI, body mass index; FT3, free-T3; FT4, free-T4; TRAb, anti-TSH receptor antibody; TgAb, anti-thyroglobulin antibody; TPOAb, anti-thyroid peroxidase antibody; MMI, thiamazole; GD, Graves’ disease. †For some patients, the time of onset is unknown and the disease duration is uncertain, the range in which the prevalence of GD can be confirmed is described as the disease duration. ‡A TSH level less than 0.005 μIU/mL was regarded as 0.005 μIU/mL. A FT-3 level more than 32.55 ng/dL was regarded as 32.55 ng/dL. A FT-4 level more than 7.77 ng/dL was regarded as 7.77 ng/dL.
The reasons for surgical treatment are listed in Table 2. One main reason was selected from the medical records of each patient. The most common reason was the side effects of medication in 19 cases (42.2%), followed by drug resistance in 15 (33.3%).
| Reasons | Number (%) |
|---|---|
| Side effects of drugs | 19 (42.2%) |
| Drug resistance | 15 (33.3%) |
| Thyroid enlargement | 5 (11.1%) |
| Pregnancy preparation | 4 (8.92%) |
| Complication of thyroid tumor | 2 (4.4%) |
A comparative analysis was conducted in which patients whose reason for undergoing surgical treatment was drug resistance were defined as the drug-resistant group (DR group), patients whose reasons were not drug resistance were defined as the non-drug-resistant group (NDR group) (Table 3), and patients who achieved remission with ATDs were defined as the remission group (Remission group) (Table 3). The median age of the 15 patients in the DR group was 51 years. There were seven women (46.7%) in the DR group, which was significantly lower than that in the NDR (p = 0.010) and Remission groups (p = 0.015). The disease duration was also significantly longer in the DR group than in the NDR group (8.0 vs. 3.0 years, respectively; p = 0.013), but not in the Remission group (p = 0.739). Thyroid-related data at the maximum FT3 level showed no significant difference between the DR and NDR or Remission group. However, the FT3/FT4 ratio was significantly higher in the DR group than the NDR (5.54 vs. 3.52, respectively; p = 0.005) or Remission groups (5.54 vs. 2.99, respectively; p < 0.001). Regarding autoantibodies, significantly higher values were observed for TRAb (39.16 vs. 13.31 IU/L, respectively; p = 0.002), but no significant differences were observed for TgAb and TPOAb, in the DR group compared with the NDR group. In contrast, TRAb (39.16 vs. 5.9 IU/L, respectively; p < 0.001) and TPOAb (389.7 vs. 16.9 IU/L, respectively; p = 0.004) were significantly higher in the DR group than the Remission group. Regarding surgery, total thyroidectomy was performed in all cases, and thyroid weight was significantly higher in the DR group compared with the NDR group (251.00 vs. 54.80 g, respectively; p < 0.001). In the Remission group, some of the thyroid ultrasound results were inaccurate; hence, thyroid weight could not be compared between these two groups. Moreover, the amount of MMI used could not be evaluated in the remission group. Given the disease history, it was not possible to match the time of evaluation for doses of MMI between the DR and Remission groups (Table 3).
| Patients’ characteristics and parameter | Number of patients or median [IQR] | p-value | ||
|---|---|---|---|---|
| Drug-resistant group (DR group) | Non-drug-resistant group (NDR group)_Remission group |
|||
| n | 15 | NDR group | 30 | |
| Remission group | 73 | |||
| Female, n | 7 (46.7%) | NDR group | 26 (86.7%) | 0.010* |
| Remission group | 59 (80.8%) | 0.009** | ||
| Age at surgical treatment, y | 51§ [25–57] | NDR group | 48§ [32–60] | 0.441 |
| Remission group | 57§§ [40–68] | 0.015* | ||
| Disease duration†, y | 8.0§ [3.5–18.0] | NDR group | 3.0 [0.4–9.3] | 0.013* |
| Remission group | 9.0§§ [3.0–14.0] | 0.739 | ||
| BMI at first visit to our hospital, kg/ m2 | 22.5 [20.9–24.5] | NDR group | 21.4 [19.2–23.7] | 0.413 |
| Remission group | 21.9 [20.0–24.0] | 0.436 | ||
| Thyroid hormone levels at the maximum FT3 value | ||||
| TSH‡, μIU/mL | 0.005 [0.005–0.006] | NDR group | 0.005 [0.005–0.005] | 0.833 |
| Remission group | 0.005 [0.005–0.006] | 0.810 | ||
| FT3‡, pg/mL | 16.07 [8.60–22.04] | NDR group | 11.34 [6.50–19.31] | 0.455 |
| Remission group | 14.56 [7.60–20.89] | 0.633 | ||
| FT4‡, ng/dL | 2.95 [1.27–4.41] | NDR group | 3.25 [2.22–6.05] | 0.262 |
| Remission group | 4.53 [2.67–7.70] | 0.017* | ||
| FT3/FT4 | 5.54 [4.08–8.53] | NDR group | 3.52 [2.74–4.27] | 0.005** |
| Remission group | 2.99 [2.51–3.64] | <0.001*** | ||
| Antibody status | ||||
| TRAb, IU/L | 39.16 [28.19–227.80] | NDR group | 13.31 [7.36–37.87] | 0.002** |
| Remission group | 5.9 [2.8–16.4] | <0.001*** | ||
| TgAb, IU/mL | 47.7 [19.9–346.5] | NDR group | 30.1 [12.9–280.4] | 0.912 |
| Remission group | 26.6 [10.0–250.8] | 0.622 | ||
| TPOAb, IU/mL | 389.7 [201.7–2,862.6] | NDR group | 55.9 [3.2–442.6] | 0.057 |
| Remission group | 16.9 [2.1–168.9] | 0.004* | ||
| Amount of MMI used before surgical treatment, mg | 20.0 [20.0–30.0] | NDR group | 16.3 [5.0–33.8] | 0.215 |
| Total thyroidectomy, n | 15 (100.0%) | NDR group | 30 (100.0%) | |
| Thyroid weight, g | 251.00 [150.35–482.50] | NDR group | 54.80 [26.48–134.00] | <0.001*** |
Abbreviations: DR groups, patients who underwent thyroidectomy due to drug resistance; NDR group, patients who underwent thyroidectomy for reasons other than drug resistance; Remission group, patients who achieved remission with ATDs; IQR, interquartile range; BMI, body mass index; FT3, free-T3; FT4, free-T4; TRAb, anti-TSH receptor antibody; TgAb, anti-thyroglobulin antibody; TPOAb, anti-thyroid peroxidase antibody; MMI, thiamazole; GD, Graves’ disease; ATDs, antithyroid drugs. §Evaluation at the time of surgery. §§Evaluation at the time of discontinuation of ATDs. †For some patients, the time of onset is unknown and the disease duration is uncertain, the range in which the prevalence of GD can be confirmed is described as the disease duration. ‡A TSH level less than 0.005 μIU/mL was regarded as 0.005 μIU/mL. A FT-3 level more than 32.55 ng/dL was regarded as 32.55 ng/dL. A FT-4 level more than 7.77 ng/dL was regarded as 7.77 ng/dL. *p < 0.05, **p < 0.01, ***p < 0.001
Table 4 shows the characteristics of each patient in the DR group. However, the thyroid weight could not be found in the surgical records of patient numbers 8, 13, and 14. Most of the patients in the DR group had a combination of long disease duration, high FT3/FT4 ratio, high TRAb values, and heavy thyroid weight.
| No. | Age, Sex | Duration† (y) | Thyroid hormone levels at the maximum FT3 levels |
Antibody status | Amount of drug used before surgical treatment |
Thyroid Weight (g) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| FT3 (pg/mL)‡ | FT4 (ng/dL)‡ | TSH (μIU/mL)‡ | FT3/ FT4 |
TRAb (IU/L) | MMI (mg) | PTU (mg) | Levothyroxine (μg) | Potassium Iodide (mg) | ||||
| 1) | 58, M | 16 | 6.59 | 1.19 | 0.005 | 5.54 | 315.20 | 25 | — | 75 | — | 222 |
| 2) | 23, F | 5 | 10.61 | 3.86 | 0.006 | 2.75 | 39.16 | — | 600 | — | 60 | 46 |
| 3) | 56, M | 20 | 23.96 | 3.83 | 0.005 | 6.26 | 25.09 | 20 | — | 75 | — | 582 |
| 4) | 57, F | 15 | 12.40 | 0.54 | 0.028 | 22.96 | 39.95 | 20 | — | 50 | — | 280 |
| 5) | 53, M | 33 | 17.59 | 2.28 | 0.005 | 7.71 | 36.05 | 30 | — | — | 100 | 480 |
| 6) | 50, M | 22 | 14.93 | 1.34 | 0.005 | 11.14 | 223.90 | 45 | — | — | — | 506 |
| 7) | 58, F | 8 | 32.55 | 7.07 | 0.005 | 4.60 | 238.20 | 25 | — | 50 | 50 | 490 |
| 8) | 25, F | 1 | 30.26 | 7.77 | 0.005 | 3.01 | 25.34 | — | 200 | — | — | *N/A |
| 9) | 32, M | 15 | 6.36 | 0.68 | 0.019 | 9.35 | 331.40 | 20 | — | 30 | 100 | 168 |
| 10) | 64, M | 4 | 16.07 | 3.67 | 0.005 | 4.38 | 40.00 | 20 | — | — | 50 | 446 |
| 11) | 24, F | 2 | 26.55 | 6.46 | 0.005 | 4.11 | 27.90 | 60 | — | — | 50 | 97.4 |
| 12) | 25, M | 2 | 20.11 | 4.96 | 0.005 | 4.05 | 39.10 | 20 | — | — | — | 212 |
| 13) | 52, M | 3 | 4.46 | 1.39 | 0.008 | 3.21 | 22.13 | 15 | — | 25 | 50 | *N/A |
| 14) | 51, F | 25 | 4.96 | 0.51 | 0.005 | 9.73 | 231.70 | 15 | — | — | 200 | *N/A |
| 15) | 22, F | 5 | 20.02 | 2.95 | 0.005 | 6.79 | 28.47 | 30 | — | — | — | 91.6 |
Abbreviations: M, male; F, female; FT3, free-T3; FT4, free-T4; TRAb, anti-TSH receptor antibody; MMI, thiamazole; PTU, propylthiouracil; GD, Graves’ disease. †For some patients, because the time of GD onset is unclear, the duration of GD that could be extracted from medical records was considered as the total duration of GD. ‡A TSH level less than 0.005 μIU/mL was regarded as 0.005 μIU/mL. A FT-3 level more than 32.55 ng/dL was regarded as 32.55 ng/dL. A FT-4 level more than 7.77 ng/dL was regarded as 7.77 ng/dL. *The value of thyroid weight could not be found from surgical records.
The relationship between thyroid weight and various indicators (FT3, FT4, FT3/FT4 ratio, and TRAb) is shown in Supplementary Fig. 1. A significant correlation was observed between thyroid weight and the FT3/FT4 ratio (r = 0.4314, p = 0.007); however, no significant correlation was observed with the other indicators.
In this study, we investigated patients with GD and severe drug resistance. In the DR group, there was a significantly higher proportion of men, higher FT3/FT4 ratio, higher TRAb titer, and greater thyroid weight than the NDR and Remission groups (Graphical Abstract). Hence, we believe that these factors may characterize patients with GD who are susceptible to drug resistance leading to inevitable surgery.
If drug treatment for GD does not result in remission after 18 months or more, there is a possibility that remission cannot be expected even if treatment is continued for a longer duration [6-10]; consequently, it is recommended to consider surgical treatment or RI therapy. However, regarding surgical cases, the median disease duration before surgical treatment was long at 4.0 years in all cases and 8.0 years in the DR group. In the NDR group, the main reasons for undergoing thyroidectomy were side effects of medication; hence, it may be assumed that the side effects developed early on the initiation of medication, resulting in surgery. Consequently, the disease duration was expected to be shorter in the NDR group. Considering this, the longer disease duration in the DR group may have been due to the aimless continuation of drug therapy in cases where it was not effective.
In the comparative study between the DR and NDR groups and between the DR and Remission groups (Table 3), no significant difference was observed in the peak value of FT3; however, significant differences were observed in the TRAb and FT3/FT4 ratio values. The TRAb titer reflects disease progression in GD and is considered an indicator of treatment efficacy, remission, and relapse. The FT3/FT4 ratio may also serve as an indicator of drug resistance. Therefore, high TRAb values and FT3/FT4 ratios strongly characterize drug-resistant GD.
Some patients with GD have high FT3/FT4 ratios, and their FT3 and FT4 levels become uncontrolled during the course of treatment. These cases are termed T3-predominant GD. T3-predominant GD is a pathology that was first described by Takamatsu et al. [11] and was originally defined in terms of the total T3 and T4 level; however, there is also a definition using FT3 and FT4 levels [12], where FT4 is below the upper limit of normal, FT3 is high, and the FT3/FT4 ratio is more than 3.3 for more than 3 months. Applying the definition of T3-predominant GD to our study population, there were 11 patients (73.3%) in the DR group and five (17.2%) in the NDR group with T3-predominant GD; hence, there were significantly more patients in the DR group than the NDR group (p < 0.001). Patients with T3-predominant GD have more difficulty in achieving therapeutic remission, recurrence is more common, and the thyroid gland is more likely to swell over the course of treatment, resulting in a higher thyroid weight, than that of the patients with normal GD [11, 13]. T3-predominant GD is characterized by an increase in thyroid enzyme activity involved in deiodination, which is necessary for the conversion of T4 to T3 [14]. Moreover, some studies also report the enhanced expression of genes related to this deiodination enzyme in T3-predominant GD [12].
The main factors associated with MMI response are daily MMI dose, pre-treatment T3 levels, and thyroid size [15]. In our study, no significant differences were observed in the daily doses of MMI between the DR and NDR groups. Accurate data on pre-treatment T3 values could not be obtained owing to the limitations described below. However, instead of thyroid size, the weight of the thyroid gland after removal was examined and it was significantly heavier in the DR group than the NDR group, which is consistent with previous studies [15].
In this study, we found a significant correlation between the weight of the excised thyroid gland and the FT3/FT4 ratio (Supplementary Fig. 1). Regarding thyroid volume and the FT3/FT4 ratio, it has been reported that a significant correlation was observed in patients with Hashimoto’s disease who were treated with levothyroxine and whose thyroid hormone levels were stabilized [16]. A similar relationship between thyroid volume and the FT3/FT4 ratio has been reported in patients after total [17] or subtotal thyroidectomy [18] and in patients treated with RI for GD [19]. Two types of deiodinases (D1 and D2) contribute to T3 production, and Maia et al. [20] suggested that D2 is the main cause of extrathyroidal T3 production in participants with euthyroid function. The serum FT3/FT4 ratio reflects the activity of deiodinase, which converts T4 to T3 by 5'-deiodination [21]. There is a positive correlation between deiodinase activity and thyroid volume [22]. These reports suggest that thyroid weight and the FT3/FT4 ratio are likely related, which is consistent with the results shown in Supplementary Fig. 1.
The present study has a few limitations. First, this was a retrospective analysis of surgical cases; hence, it was not possible to examine the characteristics of patients with ATD-resistant GD, including those undergoing RI therapy. Second, because our hospital is a tertiary medical institution, almost all patients were referred from other medical institutions. Therefore, data at the start of medication for GD was often unknown and may have been biased by various factors, such as severity at presentation. Third, this study did not consider RI therapy, which is a treatment option for patients with drug resistance. RI therapy or surgical treatment is preferable for T3-predominant GD [23]; hence, future studies including RI therapy cases may be necessary to more clearly demonstrate the characteristics of patients resistant to ATDs as it is important to thoroughly examine the patient profiles of those treated with RI therapy and ATDs.
In conclusion, we retrospectively examined patients who underwent surgical treatment for GD, and those who achieved remission with ATDs, and found that patients resistant to ATDs had longer disease durations, higher FT3/FT4 ratios and TRAb levels, and greater thyroid weights, i.e., T3-predominant GD. Notably, most patients resistant to ATDs had a combination of these factors. Continuing ineffective ATD treatment leads to thyroid enlargement that cannot be easily controlled by RI therapy, necessitating thyroidectomy. Giant goiters make surgery more difficult and increases the risk of complications, including severe bleeding. Therefore, in patients with GD and these factors, it may be necessary to switch from ATDs to surgery or RI therapy at an early stage of treatment, rather than continuing with drug treatment indefinitely.
The authors are grateful to the investigators of this retrospective observational study and the participants. We would also like to thank Editage (www.editage.jp) for English language editing.
Formal analysis: Yusuke Shibata.
Investigation: Yusuke Shibata, Ako Oiwa, Hiroki Tanaka, Satoshi Kubota, Kenichi Ito, and Mitsuhisa Komatsu.
Project administration: Yusuke Shibata.
Supervision: Mitsuhisa Komatsu.
Writing – original draft: Yusuke Shibata and Ako Oiwa.
Writing – review & editing: Yusuke Shibata and Ako Oiwa.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
None of the authors have any potential conflicts of interest associated with this research. Mitsuhisa Komatsu is a member of Endocrine Journal’s Editorial Board.
